Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.02 seconds)

The accumulation of G1 cell cycle-related proteins by resting or cycling B cells stimulated with B cell antigen receptor (BCR)- and T helper (Th) cell-derived signals is documented. Resting B cells constitutively express cyclin dependent kinase (cdk)4, cdk2 and the cyclin dependent kinase inhibitor (CKI), p27. The initiation of optimal proliferation with F(ab')2 anti-mu plus paraformaldehyde-fixed CD40 ligand-baculovirus-infected Sf9 cells (CD40L/Sf9 cells) increases accumulation of both cdk4 and cdk2 while decreasing p27 levels. B cells express cyclin D2 early during cycle progression, while cyclin D3 and E are not expressed until 18 h poststimulation and cyclin A by 24 h poststimulation. Cycling B cells express heightened levels of all these cyclins and cdks. Although neither BCR- nor CD40-mediated signals appreciably alter cycling B cell accumulation of cyclins D2, cdk4 and cdk2, the absence of BCR-derived signals results in a decreased accumulation of cyclins D3 and E. Finally, CD40-mediated signals induce resting B cells to accumulate the CKI, p21, while cycling B cells require both BCR- and CD40-mediated signals to maintain increased expression of p21. Thus, a Th cell-derived signal may impact upon both resting and cycling B cell cycle progression, at least in part, by regulating the accumulation of p21. The functional consequences of p21 accumulation as cells enter and move through the cell cycle are discussed.
Mol Immunol 1998 Jul
PMID:CD40-mediated induction of p21 accumulation in resting and cycling B cells. 982 56

Transformation of melanocytes to metastatic melanoma cells is characterized by unrestricted proliferation under growth-factor-deprived conditions, genetic loss of cyclin dependent kinase (CDK) inhibitors (CKI, e.g. p16INK4A), and aberrant production of autocrine growth factors (e.g. basic fibroblast growth factor). The latter induces increased expression of positive CDK regulators (e.g. cyclin D1) and reduced expression of additional CKIs (e.g. p27KIP1). Combined, these events lead to sustained CDK activity and hyperphosphorylation/inactivation of the retinoblastoma tumor suppressor protein (Rb). The persistent Rb phosphorylation causes the accumulation of E2F and the transcription of its target genes whose products promote cell cycle progression.
Int J Mol Med 1998 Feb
PMID:Melanomas, from the cell cycle point of view (Review). 985 45

Chronic treatment of rats with the estrogens 17beta-estradiol or diethylstilbestrol (DES) induces pituitary tumors in Fischer 344 but not Brown-Norway or Sprague-Dawley rats. Functional loss of retinoblastoma susceptibility gene product (pRb), a major regulatory protein for the G1 to S transition of the cell cycle, has been shown in several tumors. Here we report a decreased level of pRb in pituitary tumors of the Fischer 344 rat as compared with resistant Sprague Dawley and Brown-Norway strains. pRb protein levels decreased 70% in Fischer 344 rats that were treated with diethylstilbestrol for 10 weeks as compared with tumor resistant control animals. Interestingly, the F1 hybrid (Fischer 344 x Norway) showed an intermediate range of pRb protein expression as compared with those of the parental strains. pRb expression levels in nonhemorrhagic F2 (F1 x F1) rats correlated with the size of the tumors. One week withdrawal of DES increased pRb levels as compared with continuously treated rats. Also, there was a decreased association of cyclin D and cyclin dependent kinase in susceptible tumors, supporting the hypothesis of a physical and possibly functional loss of pRb in the diethylstilbestrol-induced pituitary tumor. These results suggest that the difference in pRb regulation, whether it is a direct or indirect effect of estrogen, is related to tumor resistance or susceptibility in these two rat strains.
Mol Cell Endocrinol 1998 Nov 25
PMID:Estrogen-induced rat pituitary tumor is associated with loss of retinoblastoma susceptibility gene product. 1002 66

Neurofilament proteins, the major cytoskeletal components of large myelinated axons, are highly phosphorylated by second messenger-dependent and -independent kinases. These kinases, together with tubulins and other cytoskeletal proteins, have been shown to bind to neurofilament preparations. Cdk5 and Erk2, proline-directed kinases in neuronal tissues, phosphorylate the Lys-Ser-Pro (KSP) repeats in tail domains of NF-H, NF-M, and other axonal proteins such as tau and synapsin. In neurofilament and microtubule preparations from rat brain, we demonstrated by Western blot analysis that cdk5, a neuronal cyclin dependent kinase and Erk1/2 were associated with complexes of NF proteins, tubulins and tau. Using P13(suc1) affinity chromatography, a procedure known to bind cdc2-like kinases in proliferating cells with high affinity, we obtained a P13 complex from a rat brain extract exhibiting the same profiles of cdk5 and Erk2 bound to cytoskeletal proteins. The phosphorylation activities of these preparations and the effect of the cdk5 inhibitor, butyrolactone, were consistent with the presence of active kinases. Finally, during a column fractionation and purification of Erk kinases from rat brain extracts, fractions enriched in Erk kinase activity also exhibited co-elution of phosphorylated NF-H, tubulin, tau and cdk5. We suggest that in mammalian brain, different kinases, their regulators and phosphatases form multimeric complexes with cytoskeletal proteins and regulate multisite phosphorylation from synthesis in the cell body to transport and assembly in the axon.
Brain Res Mol Brain Res 2000 Mar 29
PMID:Cdk5 and MAPK are associated with complexes of cytoskeletal proteins in rat brain. 1076 98

E2F -1 is a transcription factor that regulates cell cycle progression into S-phase. Deregulation of E2F-1 activity has been associated with cellular commitment to apoptosis. Also critical in the regulation of S-phase are the actions of the cyclin dependent kinases, Cdk2 and cdc2. Inhibition of these cyclin dependent kinases has been similarly associated with disrupting orderly S-phase progression and causing subsequent apoptosis in certain cancer cells. In this study, we examine the ability of adenovirus-mediated E2F-1 overexpression to induce apoptosis in human gastric carcinoma cells. Furthermore, we investigate the effect of the cyclin dependent kinase inhibitors, olomoucine and roscovitine, on E2F-1-mediated apoptosis in human gastric carcinoma cells. AGS and SNU-1 gastric adenocarcinoma cells were infected with adenoviral vectors expressing E2F-1 (Ad5CMVE2F-1) or control viruses expressing beta-galactosidase (Ad5CMVLacZ) or lacking a transgene (Ad5). Gastric adenocarcinoma cells were then independently treated with roscovitine or olomoucine. Finally, gastric adenocarcinoma cells were infected with the various adenoviral vectors in combination with roscovitine or olomoucine. E2F-1 overexpression resulted in an 85% reduction in cell viability at 72 h compared to controls. Combining E2F-1 overexpression with roscovitine resulted in >99% reduction in cell viability by 72 h. Overexpression of E2F-1 resulted in premature S-phase entry and G2/M arrest at 24 h, followed by apoptosis by 72 h. Combining E2F-1 overexpression with roscovitine resulted in an earlier G2/M arrest, followed by a more complete, widespread apoptotic response by 24 h. Caspase 3/CPP32 activation and PARP cleavage in response to E2F-1 overexpression, alone and in combination with roscovitine, implicate the caspase cascade in E2F-1-mediated apoptosis of gastric cancer cells. Bax levels also increased in response to E2F-1 gene transfer, alone and in combination with roscovitine. E2F-1 overexpression induces widespread apoptosis in human gastric carcinoma cells. Combining E2F-1 overexpression with cyclin-dependent kinase inhibitors results in an enhanced apoptotic response, causing nearly complete gastric tumor cell death within 72 h. E2F-1 gene therapy in combination with cyclin dependent kinase inhibitors is a potentially active chemogene therapy strategy for the treatment of human gastric cancer.
Int J Mol Med 2000 Jul
PMID:Adenovirus-mediated E2F-1 gene transfer induces an apoptotic response in human gastric carcinoma cells that is enhanced by cyclin dependent kinase inhibitors. 1085 Dec 67

Hepatoblastoma is a rare pediatric liver tumor. While much progress has been made in the treatment of the disease, very little is known about the moleculer events underlying the pathogenesis of this disease. We sought to investigate a series of hepatoblastomas for alterations in gene expression patterns with emphasis on important cell regulatory genes, including chromatin modifying enzymes, cyclin dependent kinase inhibitors, growth factors, oncogenes and cell cycle regulators. Total RNA was extracted from a series of sporadic hepatoblastomas with matched normal liver, some unmatched tumors and fetal livers, and gene expression was measured for various genes using RNase Protection Analysis (RPA). The results of this analysis show that the expression of many important regulatory genes are distinctly altered in these tumors, and a subset of tumors can be distinguished on the basis of these gene expression differences and histopathological features. Because the molecular events underlying the pathogenesis of this rare tumor are so poorly understood, this study represents a first step in determining some of the possible mechanisms involved which may provide future avenues of research.
Int J Mol Med 2000 Aug
PMID:Expression of genes involved with cell cycle control, cell growth and chromatin modification are altered in hepatoblastomas. 1089 60

Cyclin-dependent kinase 1 (CDK1), an enzyme participating in the regulation of the cell cycle, constitutes a possible target in the search for new antitumor agents. Starting from the purine derivative olomoucine and following a structure-based approach, potent inhibitors of this enzyme were rapidly identified. The molecular modeling aspects of this work are described.
J Comput Aided Mol Des 2000 Jul
PMID:Structure-based design of potent CDK1 inhibitors derived from olomoucine. 1089 13

Huanglian is an herb that is widely used in China for the treatment of gastroenteritis. We elected to determine whether huanglian could inhibit tumor cell growth by modulating molecular events directly associated with the cell cycle. Huanglian inhibited tumor growth and colony formation of gastric, colon, and breast cancer cell lines in a time- and dose-dependent manner. Cell growth was completely inhibited after 3 days of continuous drug exposure to 10 microg/ml of herb. This degree of growth inhibition was significantly greater than that observed with berberine, the major constituent of the herb. The inhibition of cell growth by huanglian was associated with up to 8-fold suppression of cyclin B1 protein. This resulted in complete inhibition of cdc2 kinase activity and accumulation of cells in G(2). The mRNA expression of cyclin B1 was not changed after huanglian treatment. There was no change in the protein expression of cyclins A or E. Therefore, the effect of huanglian on inhibiting tumor growth seems to be mediated by the selective suppression of cyclin B1, which results in the inhibition of cdc2 kinase activity. Inhibition of cyclin dependent kinase (cdk) activity is emerging as an attractive target for cancer chemotherapy. Huanglian represents a class of agents that can inhibit tumor cell growth by directly suppressing the expression of a cyclin subunit that is critical for cell cycle progression. These results indicate that traditional Chinese herbs may represent a new source of agents designed for selective inhibition of cyclin dependent kinases in cancer therapy.
Mol Pharmacol 2000 Dec
PMID:Huanglian, A chinese herbal extract, inhibits cell growth by suppressing the expression of cyclin B1 and inhibiting CDC2 kinase activity in human cancer cells. 1109 65

Transforming growth factor beta (TGF-beta) is a member of a family of cytokines that regulate differentiation and proliferation in a wide variety of tissues including the pituitary gland. In both the normal pituitary and tumorous cell lines TGF-beta1 has anti-proliferative activity, however the intracellular mechanisms responsible have not been defined. In the pituitary derived cell line GH(3), p27(Kip1), a key regulator of G(1)/S transition is not expressed, suggesting that this protein is not an effector of the anti-proliferative response following TGF-beta1 treatment. Among other TGF-beta responsive cell cycle regulators p15(Ink4b) has been shown to have anti-proliferative effects associated with cell cycle arrest in other cell types. We therefore examined p15(Ink4b) expression in response to TGFbeta-1 to determine if this cyclin dependent kinase inhibitor was responsible for anti-proliferative activity in GH(3) cells. Treatment of GH(3) cells with TGF-beta1 (0.5-30 ng/ml) showed significant dose dependent growth inhibition (P<0.001) as assessed by viable cell counts. Maximum growth inhibition (66%) was observed following treatment with 2 ng/ml TGF-beta1. FACS analysis carried out in parallel with the growth studies showed treatment was associated with a decrease in the proportion of cells in S-phase (22-9%) and a significant increase in the G(1) fraction from 58 to 75% relative to controls (P<0.001). The absence of a sub G(1) fraction and reversibility of the G(1) arrest over three cycles showed that these changes were not due to either an apoptotic response or cytoxicity, respectively. Semi-quantitative RT-PCR and Western blot analysis showed no change in the expression level of cyclin dependent kinase 4 (CDK4), p16(Ink4a) or p21(Cip1). However, p15(Ink4b) mRNA and protein levels showed a 10 and 8 -fold induction, respectively. Increased levels of p15(Ink4b) were accompanied by a shift in the phosphorylation status of pRb toward its active hypophosphorylated form. Furthermore, studies of the kinetics of p15(Ink4b) induction showed that arrest of cells in G(1) is preceded by induction of p15(Ink4b) mRNA and protein. These investigations would suggest that p15(Ink4b) is a functional effector of TGF-beta1 mediated cell cycle arrest in GH(3) cells. However, our present studies cannot determine if it is the sole mediator. Identification of intracellular target(s) that mediate responses to anti-proliferative signals will increase our understanding of these pathways and aberrations responsible for their dysfunction in tumorigenesis.
Mol Cell Endocrinol 2001 May 15
PMID:Decreased proliferation and cell cycle arrest in neoplastic rat pituitary cells is associated with transforming growth factor-beta1-induced expression of p15/INK4B. 1136 40

In MCF-7 breast cancer cells, the insulin-like growth factor 1 receptor (IGF-1R) and the oestrogen receptor (ER) are coexpressed and the two signalling systems are engaged in a crosstalk that results in synergistic growth. However, coupling between the signalling cascades is poorly understood. Oestradiol enhances IGF-1R signalling by inducing the expression of insulin receptor substrate 1 (IRS-1), a substrate of the IGF-1R. Oestradiol induced expression of IRS-1 results in enhanced tyrosine phosphorylation of IRS-1 after IGF-1 stimulation, followed by enhanced mitogen activated protein kinase, phosphoinositide 3' kinase, and Akt activation. Oestradiol can also potentiate the effect of IGF-1 on the expression of cyclin D1 and cyclin E, and on the phosphorylation of the retinoblastoma protein (RB). These effects are greatly diminished in SX13 cells, which exhibit a 50% reduction in IGF-1R expression but few functional IGF-1Rs at the surface. Oestradiol and IGF-1 regulate the expression of two cyclin dependent kinase inhibitors, p21 and p27, differently. Whereas IGF-1 increases p21 expression and reduces p27 expression, oestradiol has no effect on p21. In summary, in MCF-7 cells, oestrogen potentiates the effect of IGF-1 on IGF-1R signalling and its effects on certain cell cycle components.
Mol Pathol 2001 Jun
PMID:Insulin-like growth factor 1 and oestradiol promote cell proliferation of MCF-7 breast cancer cells: new insights into their synergistic effects. 1137 26


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